Review articleMechanisms of multiple chemical sensitivity
Introduction
“Disease” can be a pathologic process, and not all persons with a disease are ill. Symptoms of illness associated with a disease may be manifest or persist after the disease has disappeared. Many factors, including personal characteristics and social circumstances, can be responsible for sensitivity to, and recovery from, disease and illness (Cluff, 1991). There are many different neurological and psychiatric syndromes that follow acute illness, but their clinical pictures and pathogenesis are poorly understood.
One such condition that has received attention over the past decade is the issue of low level chemical exposures and the effects they may cause. While conventional toxicological concepts can explain the effects of elevated toxic exposures, the issue of effects from low level exposures is a relatively new area of study.
One of the problems in dealing with a toxic material is that if dose–response information is available, it usually refers to high level exposures at the upper end of the relationship, as effects are more likely to be evident. However, an absence of effect is usually not considered to be very informative. Indeed, in the absence of appropriate dose–response information, an absence of effect should not be concluded as being the effect of absence. An important emerging area of toxicology is the investigation of the biological effects of low level exposures (BELLE), that is, effects at the lower end of the dose–response relationship (Calabrese, 1992, Calabrese, 1994, Davis and Calabrese, 1998).
Historically, a syndrome called neurasthenia or “American nervousness” was described in 1880, which has many features of chemical sensitivity. Modern attempts to deal with the “chemical susceptibility problem” began in the 1950s, with the original work of Randolph (1962). A model of chemical sensitivity was proposed, consisting of the inability of the body to adapt to chemicals, and the development of responsiveness to extremely low concentrations after sensitisation in the mid-1950s. Early research investigated food intolerances.
The numbers of cases of people with such a chemical sensitivity continues to grow, and the possible mechanisms that might underlie such a condition will be described in this article.
The relationship between dose and response forms the basis of one of the fundamental toxicological principles, the dose–response relationship (see the thick curve in Fig. 1). That is, as dose (or exposure) increases, the proportion of affected individuals (or the intensity of the effect) increases. This curve can be used to explain most toxicological phenomena (WHO, 1978).
As well as conventional responses to toxic exposures, it is also recognised that some people (perhaps up to 10–20% of the population) can show allergic responses to lower levels of chemical exposures (as shown in the dashed line in Fig. 1). Allergy is a particular type of toxic response, mediated through the immune system. Individuals showing allergic reactions are generally predisposed to such responses, the predisposition often being genetically based. Further, these responses can be identified through measures of immunological or allergic function.
However, a third category of response exists, in an even smaller group of people (maybe 0.5–2% of the population) of a hypersensitivity or idiosyncratic sensitivity to chemicals at very low exposures, for which physiological or medical indicators are not yet available (shown in the thin line in Fig. 1). The terms hypersensitivity and idiosyncratic describe separate responses. The individual who is exposed to, for example solvent chemicals, can show a range of signs and symptoms. Solvents produce effects in a range of body systems, for example, the nervous system, liver and kidneys, but not in other body systems, for example, in the skeletal system. It could be concluded that an individual showing symptoms of toxicity in the nervous system (for example, neurobehavioural effects) at low exposure to solvents was hypersensitive, as the nervous system is a target organ. However, symptoms of toxicity in the skeletal system from solvent exposure are more likely be an idiosyncratic response because solvents do not normally affect the skeleton. For this reason, it should be concluded in hypersensitivity responses not that the possibility of such symptoms is remote, but that the dose–response relationship needs to be shifted to the left to take into account such effects.
Lastly, because the dose–response relationship is based on the normal distribution (or at least the log normal distribution), any such relationship approaches zero asymptotically. Arguments that inclusion of chemical sensitivity and hypersensitivity effects require a paradigm shift (Staudenmayer, 2001) or lack evidence of a threshold (Doull, 1996) are unnecessary. Given a sufficiently large population, it is possible that hypersensitive individuals are part of a very long tail approaching zero on the conventional dose–response curve.
It is customary to call the individual who responds adversely to low exposures to chemicals as being “sensitive”. While a chemically sensitive individual may arise in any group of individuals, there are four main types who contain individuals in which heightened reactivity to chemical exposures has been reported:
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industrial workers who are exposed occupationally to chemicals as part of their daily activities;
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office workers working in tight buildings;
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individuals who may be located in areas of contamination (such as contaminated sites or close to known sources of pollution); and
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individuals who, for one reason or another, received an unexpectedly debilitating exposure to a chemical.
Table 1 (modified from Ashford and Miller, 1991) outlines the exposure conditions and demographics of these groups.
Although the condition that affects the individual who is sensitive to low exposures to chemicals was known by a variety of terms for many years (including environmental illness, hypersensitivity syndrome, twentieth century disease, total allergy syndrome, ecological illness and chemical sensitivity problem (Sandler, 1993)), the name multiple chemical sensitivity (MCS) was introduced in the late 1980s, when the first articles on MCS were published (Cullen, 1987, Hilleman, 1991).
Until that time, there was a lack of a clear definition as to what MCS was, as several medical specialities squabbled about whether MCS was a medical condition, and if so, how it could be diagnosed. Some of the more divisive infighting has been between the allergists and immunologists on one side and the clinical ecologists on the other. This controversy made it difficult for patients to find objective information about the issue, and impeded their ability to resolve MCS-related problems at the workplace, insurance or litigation levels. However, the name MCS is now well established (Cullen, 1997), although debate about whether MCS is a real disease continues in some sectors of the health care profession.
Later, MCS-like conditions have also been reported, such as Gulf War Syndrome (Reid et al., 2001) and Aerotoxic Syndrome (Winder and Balouet, 2000).
Section snippets
Diagnosis of MCS
Conditions in which physical symptoms are unsupported by physical findings and have diagnostic labels that describe the disorder without indicating either cause or pathology are especially troubling for the medical practitioner. However, a working definition for MCS was established in 1987 (Cullen, 1987). This definition, subsequently modified, suggested a grouping of effects in workers who had been exposed to low levels of several chemicals. A Symposium on MCS was held by the Association of
Conclusions
There are an increasing number of people showing unspecific symptoms related to low level occupational (or sometimes environmental) chemical exposures.
With regard to the links between exposure and adverse effect, the body has a substantial number of mechanisms that allow re-establishment of normal function after disruption or dysfunction. Exposure to toxic chemicals may cause a disruption in normal function, which in turn may activate individual defence mechanisms (depending on the type of
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